EP0641795B9 - Carbapenem derivative - Google Patents
Carbapenem derivative Download PDFInfo
- Publication number
- EP0641795B9 EP0641795B9 EP92913257A EP92913257A EP0641795B9 EP 0641795 B9 EP0641795 B9 EP 0641795B9 EP 92913257 A EP92913257 A EP 92913257A EP 92913257 A EP92913257 A EP 92913257A EP 0641795 B9 EP0641795 B9 EP 0641795B9
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- alkyl group
- hydrogen atom
- compound
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical class C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 title abstract 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 20
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 109
- -1 methoxyethyl Chemical group 0.000 claims description 49
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 41
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000005633 phthalidyl group Chemical group 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 42
- 239000001257 hydrogen Substances 0.000 abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 9
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 6
- 241000589517 Pseudomonas aeruginosa Species 0.000 abstract description 4
- 239000003242 anti bacterial agent Substances 0.000 abstract description 4
- 102000004190 Enzymes Human genes 0.000 abstract description 3
- 108090000790 Enzymes Proteins 0.000 abstract description 3
- 102000004157 Hydrolases Human genes 0.000 abstract description 3
- 108090000604 Hydrolases Proteins 0.000 abstract description 3
- WKDDRNSBRWANNC-ATRFCDNQSA-N Thienamycin Chemical compound C1C(SCCN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 WKDDRNSBRWANNC-ATRFCDNQSA-N 0.000 abstract description 3
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 abstract description 3
- 230000003115 biocidal effect Effects 0.000 abstract description 3
- YKMONJZIUAOVEM-WDSKDSINSA-N 1beta-methylcarbapenem Chemical class C[C@H]1C=CN2C(=O)C[C@@H]12 YKMONJZIUAOVEM-WDSKDSINSA-N 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 210000003734 kidney Anatomy 0.000 abstract description 2
- 231100000417 nephrotoxicity Toxicity 0.000 abstract description 2
- 150000002431 hydrogen Chemical class 0.000 abstract 3
- 230000003389 potentiating effect Effects 0.000 abstract 2
- 241000894006 Bacteria Species 0.000 abstract 1
- 206010029155 Nephropathy toxic Diseases 0.000 abstract 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- 230000002411 adverse Effects 0.000 abstract 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 230000007694 nephrotoxicity Effects 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 238000006243 chemical reaction Methods 0.000 description 76
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 72
- 230000002829 reductive effect Effects 0.000 description 62
- 239000002904 solvent Substances 0.000 description 62
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 238000001704 evaporation Methods 0.000 description 53
- 230000008020 evaporation Effects 0.000 description 52
- 238000005481 NMR spectroscopy Methods 0.000 description 51
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 50
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 40
- 239000007864 aqueous solution Substances 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 229910052938 sodium sulfate Inorganic materials 0.000 description 33
- 235000011152 sodium sulphate Nutrition 0.000 description 33
- 239000000203 mixture Substances 0.000 description 32
- 238000010898 silica gel chromatography Methods 0.000 description 31
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 238000001816 cooling Methods 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
- 238000000746 purification Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 238000001914 filtration Methods 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical compound OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
- 235000017557 sodium bicarbonate Nutrition 0.000 description 17
- 229960004106 citric acid Drugs 0.000 description 16
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 125000006239 protecting group Chemical group 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 12
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 239000008363 phosphate buffer Substances 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 7
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 7
- 229910003446 platinum oxide Inorganic materials 0.000 description 7
- MHSGOABISYIYKP-UHFFFAOYSA-N (4-nitrophenyl)methyl carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(COC(Cl)=O)C=C1 MHSGOABISYIYKP-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 150000002148 esters Chemical group 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical group O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 6
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- UOHJEDBIRDIRSB-UHFFFAOYSA-N (4-methoxyphenyl)methyl piperazine-1-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)N1CCNCC1 UOHJEDBIRDIRSB-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 5
- 238000010531 catalytic reduction reaction Methods 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 239000002198 insoluble material Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011343 solid material Substances 0.000 description 5
- 239000002132 β-lactam antibiotic Substances 0.000 description 5
- 229940124586 β-lactam antibiotics Drugs 0.000 description 5
- XEZKLVYMADZCFU-SFTDATJTSA-N (4-nitrophenyl)methyl (2s,4s)-4-benzoylsulfanyl-2-(piperazine-1-carbonyl)pyrrolidine-1-carboxylate Chemical compound C1=CC([N+](=O)[O-])=CC=C1COC(=O)N1[C@H](C(=O)N2CCNCC2)C[C@H](SC(=O)C=2C=CC=CC=2)C1 XEZKLVYMADZCFU-SFTDATJTSA-N 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 229920001281 polyalkylene Polymers 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- VXSXAAALVLUDAV-IRXDYDNUSA-N (2s,4s)-4-benzoylsulfanyl-1-[(4-nitrophenyl)methoxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@H](C[C@H]1C(=O)O)SC(=O)C=2C=CC=CC=2)N1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 VXSXAAALVLUDAV-IRXDYDNUSA-N 0.000 description 3
- YKJCLNYKRUDGQA-GGAORHGYSA-N (4-methoxyphenyl)methyl 4-[(2s,4r)-4-hydroxy-1-[(4-nitrophenyl)methoxycarbonyl]pyrrolidine-2-carbonyl]piperazine-1-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)N1CCN(C(=O)[C@H]2N(C[C@H](O)C2)C(=O)OCC=2C=CC(=CC=2)[N+]([O-])=O)CC1 YKJCLNYKRUDGQA-GGAORHGYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- UIJGNTRUPZPVNG-UHFFFAOYSA-N benzenecarbothioic s-acid Chemical compound SC(=O)C1=CC=CC=C1 UIJGNTRUPZPVNG-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 description 2
- AVUYDXAPBJERDH-JTQLQIEISA-N (2s)-2-hydroxy-4-[(4-nitrophenyl)methoxycarbonylamino]butanoic acid Chemical compound OC(=O)[C@@H](O)CCNC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 AVUYDXAPBJERDH-JTQLQIEISA-N 0.000 description 2
- MDVDXPLKDZPQQB-VMPREFPWSA-N (4-methoxyphenyl)methyl 4-[(2s,4s)-4-benzoylsulfanyl-1-[(4-nitrophenyl)methoxycarbonyl]pyrrolidine-2-carbonyl]piperazine-1-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)N1CCN(C(=O)[C@H]2N(C[C@H](C2)SC(=O)C=2C=CC=CC=2)C(=O)OCC=2C=CC(=CC=2)[N+]([O-])=O)CC1 MDVDXPLKDZPQQB-VMPREFPWSA-N 0.000 description 2
- NSTLOENCEWRMIL-GDLZYMKVSA-N (4-methoxyphenyl)methyl 4-[2-[(2s)-3-[(4-nitrophenyl)methoxy]-2-[(4-nitrophenyl)methoxycarbonylamino]-3-oxopropyl]sulfanylacetyl]piperazine-1-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)N1CCN(C(=O)CSC[C@@H](NC(=O)OCC=2C=CC(=CC=2)[N+]([O-])=O)C(=O)OCC=2C=CC(=CC=2)[N+]([O-])=O)CC1 NSTLOENCEWRMIL-GDLZYMKVSA-N 0.000 description 2
- BOBQRMOOSVBPAV-UHFFFAOYSA-N (4-methoxyphenyl)methyl 4-[2-[(4-nitrophenyl)methoxycarbonylamino]acetyl]piperazine-1-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)N1CCN(C(=O)CNC(=O)OCC=2C=CC(=CC=2)[N+]([O-])=O)CC1 BOBQRMOOSVBPAV-UHFFFAOYSA-N 0.000 description 2
- MIAYNDCENHIBMX-XMMPIXPASA-N (4-nitrophenyl)methyl (2s)-3-[(4-methoxyphenyl)methylsulfanyl]-2-[(4-nitrophenyl)methoxycarbonylamino]propanoate Chemical compound C1=CC(OC)=CC=C1CSC[C@H](C(=O)OCC=1C=CC(=CC=1)[N+]([O-])=O)NC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 MIAYNDCENHIBMX-XMMPIXPASA-N 0.000 description 2
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- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- ZFXMMFDWDHIHGS-JJCDCTGGSA-N COC1=CC=C(C[S@@+](C[C@@H]2C([O-])=O)CN2C(OCC(C=C2)=CC=C2[N+]([O-])=O)=O)C=C1 Chemical compound COC1=CC=C(C[S@@+](C[C@@H]2C([O-])=O)CN2C(OCC(C=C2)=CC=C2[N+]([O-])=O)=O)C=C1 ZFXMMFDWDHIHGS-JJCDCTGGSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
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- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LBWUXVCSHXPSRB-PBYQXAPXSA-N [N+](=O)([O-])C1=CC=C(COC(=O)N2[C@@H](C[S@@+](C2)CC2=CC=C(C=C2)OC)C(=O)Cl)C=C1 Chemical compound [N+](=O)([O-])C1=CC=C(COC(=O)N2[C@@H](C[S@@+](C2)CC2=CC=C(C=C2)OC)C(=O)Cl)C=C1 LBWUXVCSHXPSRB-PBYQXAPXSA-N 0.000 description 1
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 108700003601 dimethylglycine Proteins 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- ANLRDBWTGZFMOC-KBPBESRZSA-N ethyl (2s,4s)-4-[(4-methoxyphenyl)methylsulfanyl]pyrrolidine-2-carboxylate Chemical compound C1N[C@H](C(=O)OCC)C[C@@H]1SCC1=CC=C(OC)C=C1 ANLRDBWTGZFMOC-KBPBESRZSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229940078490 n,n-dimethylglycine Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention relates to novel antibiotics having a carbapenem skelton.
- Thienamycin having a carbapenem skelton has been regarded as a promising new antibiotic since its discovery in 1976, because it is effective upon bacterial strains which are resistant against prior art antibiotics and it can exhibit excellent antibacterial activity.
- thienamycin and various other carbapenem derivatives reported thereafter have to be used as a mixed preparation with a dehydropeptidase (DHP) inhibitor, because they are not only physico-chemically unstable but also apt to be decomposed by DHP and the like enzyme in the kidney, thereby causing side-effects such as renal toxicity.
- DHP dehydropeptidase
- JP-A-60-233076 discloses 1- ⁇ -methylcarbapenem compounds which are stable against ⁇ -lactamase producing strains, have physico-chemically stable nature and exhibit strong antibacterial activity. These compounds, however, are still unsatisfactory in terms of their stability against DHP and antibacterial activity.
- the inventors of the present invention have conducted intensive studies with the aim of finding a carbapenem derivative having more excellent properties and, as the results, have accomplished the present invention by finding a compound which is effective upon various bacterial strains including Pseudomonas aeruginosa , excellent in terms of safety and stability against hydrolases such as DHP and the like.
- the present invention relates to a carbapenem derivative represented by the following general formula (I), and a salt thereof; wherein
- Preferred compounds are 1R,5S,6S,8R-6-(1-hydroxyethyl)-1-methylcarbapenem derivatives.
- carbapenem as used herein means a compound having the following structural nucleus, and the present invention relates to carbapenem derivatives in which various types of substituent groups are attached to this nucleus.
- lower alkyl group as used herein means an alkyl group having 1 to 6 carbon atoms (those having 1 to 6 carbon atoms will be expressed respectively as C1-C6 in the following, as well as other cases with different carbon numbers), such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like.
- R 1 represents a lower alkyl group or a hydroxyl group-substituted product thereof, namely a hydroxyalkyl group, which may also have a protecting group.
- 1-hydroxyethyl group is preferred, especially when 1-hydroxyethyl group is linked to the 6-positioned carbon atom of the carbapenem skelton in the form of S-configulation and its hydroxyl group is linked to the 1-position of the ethyl group (generally called the carbapenem 8-position) in the form of R-configulation.
- R 2 represents a hydrogen atom or a lower alkyl group, preferably a straight- or branched-chain C1-C4 lower alkyl group such as methyl, ethyl or propyl, more preferably a methyl group.
- such groups may preferably have R-configulation with regard to the 1-positioned carbon atom of the carbapenem skelton.
- R 3 represents a carboxyl group which may be esterified.
- the ester residue include straight-or branched-chain C1-C6 alkyl groups such as methyl, ethyl, isobutyl or tertiary butyl; C1-C6 alkoxy C1-C6 alkyl groups such as methoxymethyl or methoxyethyl; C2-C7 aliphatic acyloxymethyl groups such as pivaloyloxymethyl; phthalidyl group and the like.
- ester residues useful as carboxyl group-protecting groups at the time of the synthesis reaction include a p-nitrobenzyl group, an allyl group, and the like.
- Metabolizable ester residues may also be used, with their preferred examples including a pivaloyloxymethyl group, a phthalidyl group, an acetoxycarbonyloxymethyl group, and the like.
- Carboxyl group may be in the form of carboxylate anion in relation to other substituent groups, salt, and the like.
- R 4 represents a hydrogen atom, a straight- or branched-chain C1-C6 lower alkyl group such as methyl, ethyl or propyl, an amino group protecting group which is commonly used in ⁇ -lactam antibiotics, such as p-nitrobenzyloxycarbonyl, t-butoxycarbonyl or allyloxycarbonyl, and the like.
- R 5 and R 6 which may be the same or different, each represents a hydrogen atom, a hydroxyl group, a lower alkyl group, a hydroxy lower alkyl group or a halogen atom.
- R 5 and R 6 may together form a polyalkylene chain having 2 to 6 carbon atoms, and form a cyclic structure together with the carbon atom to which R 5 and R 6 are attached.
- R 7 represents a hydrogen atom, a lower alkyl group, a carboxyl group, a carbamoyl group, a carboxyl group which may have a protecting group, or a substituted carbamoyl groups represented by the following partial structural formula.
- each of R 71 and R 72 represents a hydrogen atom or a lower alkyl group. These may together form a polyalkylene chain having 2 to 6 carbon atoms, and form a cyclic structure together with the nitrogen atom to which R 71 and R 72 are attached.
- R 8 represents a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group.
- R 7 and R 8 may together form a polyalkylene chain having 2 to 6 carbon atoms, and form a cyclic structure together with the carbon atom to which R 7 and R 8 are attached.
- Each of R 9 and R 10 represents an amino group-protecting group, a hydrogen atom or a lower alkyl group.
- Preferred examples of the amino group-protecting group include those which are usually used in ⁇ -lactam antibiotics, for example, p-nitrobenzyloxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, and the like.
- Z represents a single bond or an oxygen atom (-O-) or a sulfur atom (-S-), or a partial structure represented by-CR 11 R 12 -, -NR 13 CO-, -CONR 14 - or -NR 15 -.
- R 11 and R 12 which may be the same or different, each represents a hydrogen atom, a hydroxyl group, a lower alkyl group, a hydroxy lower alkyl group such as hydroxymethyl or hydroxtethyl, or a halogen atom.
- R 11 and R 12 may together form a polyalkylene chain having 2 to 6 carbon atoms, and form a cyclic structure together with the carbon atom to which R 11 and R 12 are attached.
- Each of R 13 and R 14 represents a hydrogen atom or a lower alkyl group.
- R 15 represents an amino group protecting group, a hydrogen atom or a lower alkyl group.
- Preferred examples of the amino group protecting group include those which are commonly used in ⁇ -lactam antibiotics, for example, p-nitrobenzyloxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl and the like.
- Each of m and n is an integer of 0 to 6.
- the compound of the present invention and some of the intermediates may have tautomeric structures. Though these structures are shown by a single structural formula in this specification, it should be understood not to be limited thereto.
- the compound of the present invention may be used in the form of a pharmacologically acceptable salt.
- a pharmacologically acceptable salt examples include carboxylic acid nontoxic salts such as sodium, potassium, aluminium, magnesium and the like metal salts; ammonium salt; triethylamine salt, procaine salt and benzylamine salt, as well as salts with other amines which are commonly used for the salt formation of penicillins and cephalosporins.
- carboxylic acid nontoxic salts such as sodium, potassium, aluminium, magnesium and the like metal salts
- ammonium salt such as sodium, potassium, aluminium, magnesium and the like metal salts
- triethylamine salt such as sodium, potassium, aluminium, magnesium and the like metal salts
- triethylamine salt such as sodium, potassium, aluminium, magnesium and the like metal salts
- triethylamine salt such as sodium, potassium, aluminium, magnesium and the like metal salts
- triethylamine salt such as sodium, potassium
- the carbapenem derivative of the present invention may also be converted to a pharmacologically acceptable acid addition salt, for example, with an inorganic acid such as hydrochlroic acid, hydrobromic acid, phosphoric acid or sulfuric acid, or with an organic acid such as acetic acid, citric acid, succinic acid, ascorbic acid or methanesulfonic acid.
- an inorganic acid such as hydrochlroic acid, hydrobromic acid, phosphoric acid or sulfuric acid
- an organic acid such as acetic acid, citric acid, succinic acid, ascorbic acid or methanesulfonic acid.
- hydrochloride and sulfate are particularly preferred.
- the inventive compound may also be used in the form of various solvates such as a hydrate.
- the compound of the present invention can exhibit excellent antibacterial property against not only Escherichia coli , Proteus, Klebsiella , Enterobacter, Salmonella, Serratia , Streptococcus , Staphylococcus and the like but also Pseudomonas aeruginosa , it can be applied efficiently to the treatment of various infectious diseases such as respiratory infection, secondary infection caused by injury lesion, burn injury or operative wound and purulent diseases.
- the compound of the present invention can be formulated as pharmaceutical preparations in the usual way formulated with commonly used pharmaceutical additives such as a carrier, a stabilizer, a solubilizing agent and a filler. It may be administered by various routes such as oral administration in the dosage form of tablets, pills, capsules, granules or the like and parenteral administration in the dosage form of intravenous injections, intramuscular injections, suppositories and the like, of which intravenous injection is generally preferable.
- pharmaceutical additives such as a carrier, a stabilizer, a solubilizing agent and a filler.
- the dairy dose may be administered in an approximate dose of 100 mg to 3 g per adult once a day or dividing the dairy dose into several times.
- the dose may be changed optionally depending on the age and sex of each patient and symptoms of the disease to be treated.
- the compound of the present invention can be produced' in accordance with a process represented by the following reaction scheme.
- An reactive intermediate (III) can be derived by a reaction of compound (II) (R 1 , R 2 and R 3 in the formula are the same groups described in the foregoing) with diphenylphosphoryl chloride according to a known method (D.H. Shih et al., Heterocycles, 21 , 29 (1984)) or a modified method thereof.
- This reaction may be carried out preferably in the presence of an alkylamine such as triethylamine, diisopropylethylamine or the like, an alicyclic amine such as 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), N-methylmorpholine or the like, an organic base such as quinuclidine, 3-quinuclidinol or the like, an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or the like, a metal alkolate such as potassium-t-butoxide, sodium methoxide or the like or sodium amide; among these, diisopropylethylamine or DBU is particularly preferred.
- an alkylamine such as triethylamine, diisopropylethylamine or the like
- an alicyclic amine such as 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), N-methylmorpholine
- this reaction may be carried out in a solvent which does not exert bad influences upon the starting materials and the product, with illustrative examples of the solvent including ketones such as acetone, methylethylketone and the like, acetonitrile, dimethylformamide (DMF), dimethylacetamide, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dichloromethane and chloroform, as well as optionally combined mixtures thereof.
- the solvent including ketones such as acetone, methylethylketone and the like, acetonitrile, dimethylformamide (DMF), dimethylacetamide, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dichloromethane and chloroform, as well as optionally combined mixtures thereof.
- the reaction temperature may be in the range of from -50°C to room temperature, preferably from -40°C to 0°C.
- the reaction may be carried out for a period of from 15 minutes to 1 day, preferably from 30 minutes to 8 hours.
- the thiol compound (IV) can be produced by a method of Reference Examples described later.
- the reaction with the thiol compound (IV) having a high reactivity proceeds well in the presence of a base, though the reaction also progresses without a base.
- the bases illustrated in the foregoing in relation to the preceding reaction step may also be used in this reaction, of which diisopropylethylamine and DBU are particularly preferred.
- Such a base may be used preferably in an amount equivalent to the thiol compound, but, when the thiol compound is in the form of an acid addition salt, a good result may be obtained by supplementing an additional amount of the base necessary for the neutralization of the addition acid.
- This reaction may also be carried out in a solvent which does not exert bad influences upon the material compounds and the product, and the solvents described in the preceding reaction step may be used as a solvent.
- the solvents described in the preceding reaction step may be used as a solvent.
- the compound of formula (IV) may be used in an amount of from 1 to 3 equivalent, preferably from 1 to 2 equivalent, to the compound of formula (III).
- the reaction temperature may be in the range of from -50°C to room temperature, preferably from -40°C to 0°C.
- the reaction may be carried out for a period of from 30 minutes to 1 day, preferably from 1 to 6 hours.
- the substitution product can be isolated by usually manner means and, if necessary, purified by subjecting to a silica gel column chromatography using chloroform, ethyl acetate, dichloromethane, methanol'or a mixture thereof.
- substitution reaction product When the substitution reaction product has a protecting group, it can be removed if desired. Its removal may be effected by reductive hydrogenolysis, chemical reduction or hydrolysis using an acid, a base or an enzyme.
- R 3 in the general formula (I) When the substituent group R 3 in the general formula (I) is esterified and has for example a p-nitrobenzyl group, a benzyl group, a benzhydryl group or a 2-naphthylmethyl group, such a compound can be transformed to a carbapenem derivative in which R 3 in the general formula (I) is a carboxyl group or a carboxylate anion, by a deprotection reaction through catalytic reduction in the presence of a known metal catalyst such as palladium on charcoal, platinum oxide or the like.
- a known metal catalyst such as palladium on charcoal, platinum oxide or the like.
- reaction may be carried out in a reaction solvent such as dioxane, THF, water, a buffer solution or a mixture thereof, preferably aqueous dioxane or a mixed solvent consisting of a phosphate buffer and THF, under a hydrogen pressure of from 1 to 5 atmospheric pressure, at a temperature of from 0 to 50°C, preferably from 10 to 30°C, and for a period of from 30 minutes to 16 hours, generally from 10 minutes to 1 hour.
- a reaction solvent such as dioxane, THF, water, a buffer solution or a mixture thereof, preferably aqueous dioxane or a mixed solvent consisting of a phosphate buffer and THF
- R 3 in the compound (I) is a p-nitrobenzyloxycarbonyl group
- it may be allowed to react with ammonium chloride aqueous solution and iron powder in a water soluble organic solvent such as THF or dioxane to yield the compound of interest in which R 3 is a carboxyl group or a carboxylate anion, or when R 3 is an allyloxycarbonyl group
- the compound of interest may be obtained by treating it with tetrakistriphenylphosphinepalladium (0), triphenylphosphine and 2-ethylhexanoic acid in an aprotic solvent such as THF or dichloromethane.
- the catalytic reduction reaction may be carried out in a solvent such as dioxane, THF, water, a buffer solution or a mixture thereof, preferably aqueous dioxane or a mixed solvent consisting of a phosphate buffer and THF, under a hydrogen pressure of from 1 to 5 atmospheric pressure, at a temperature of from 0 to 50°C, preferably from 10 to 30°C, and for a period of from 30 minutes to 16 hours, generally from 10 minutes to 1 hour, thereby obtaining the carbapenem derivative (I).
- a solvent such as dioxane, THF, water, a buffer solution or a mixture thereof, preferably aqueous dioxane or a mixed solvent consisting of a phosphate buffer and THF
- the compound of interest can be purified by usually used isolation means, namely by extraction and subsequent concentration, followed, if necessary, by recrystallization, reprecipitation, column chromatography and the like.
- the compound (I) can be made into a highly purified form by its crystallization, and such a purpose can be achieved sometimes with a high efficiency when the compound is in a salt form.
- the salt is not necessarily a non-toxic acid addition salt, but the compound of interest can be obtained with a high purity by crystallizing it as a toxic salt, purifying the salt and then removing the acid or converting the salt into a pharmacologically acceptable salt.
- Esters which is metabolizable in vivo can be produced by making R 3 in the compound of general formula (I) into an esterified form in accordance with a means usually used in the synthesis of penicillins and cephalosporins (see for example, J. Med. Chem ., 13 , 607 (1970)), or by subjecting the carboxyl group or carboxylate anion of the compound to esterification.
- R 4 is a p-nitrobenzyloxycarbonyl group.
- the present invention can provide an antibiotic which is effective upon various bacterial strains including Pseudomonas aeruginosa , excellent in terms of safety and stable against hydrolases such as DHP and the like.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP14846991 | 1991-06-20 | ||
JP148469/91 | 1991-06-20 | ||
JP14846991 | 1991-06-20 | ||
JP3105492 | 1992-02-18 | ||
JP3105492 | 1992-02-18 | ||
JP31054/92 | 1992-02-18 | ||
PCT/JP1992/000790 WO1993000344A1 (en) | 1991-06-20 | 1992-06-19 | Carbapenem derivative |
Publications (4)
Publication Number | Publication Date |
---|---|
EP0641795A4 EP0641795A4 (en) | 1994-06-09 |
EP0641795A1 EP0641795A1 (en) | 1995-03-08 |
EP0641795B1 EP0641795B1 (en) | 2002-09-25 |
EP0641795B9 true EP0641795B9 (en) | 2003-01-29 |
Family
ID=26369502
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP92913257A Expired - Lifetime EP0641795B9 (en) | 1991-06-20 | 1992-06-19 | Carbapenem derivative |
Country Status (15)
Country | Link |
---|---|
US (1) | US5559224A (ja) |
EP (1) | EP0641795B9 (ja) |
JP (1) | JP3048196B2 (ja) |
KR (1) | KR100189667B1 (ja) |
AT (1) | ATE224897T1 (ja) |
AU (1) | AU659172B2 (ja) |
CA (1) | CA2111974C (ja) |
DE (1) | DE69232791T2 (ja) |
DK (1) | DK0641795T3 (ja) |
ES (1) | ES2184731T3 (ja) |
FI (1) | FI101537B (ja) |
NO (1) | NO303636B1 (ja) |
RU (1) | RU2091381C1 (ja) |
TW (1) | TW201747B (ja) |
WO (1) | WO1993000344A1 (ja) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2026424A6 (es) * | 1991-02-26 | 1992-04-16 | Play Sa | Cuna infantil plegable. |
EP0882728B1 (en) * | 1995-12-21 | 2002-09-04 | Sankyo Company Limited | 1-methylcarbapenem derivatives |
WO2001057041A1 (fr) * | 2000-01-31 | 2001-08-09 | Sankyo Company, Limited | Composes 1-methylcarbapedem |
IN191798B (ja) | 2000-11-03 | 2004-01-03 | Ranbaxy Lab Ltd | |
NZ531174A (en) * | 2001-09-26 | 2005-09-30 | Merck & Co Inc | Process for reducing the levels of organic solvents in carbapenem compounds |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6019787A (ja) * | 1983-07-12 | 1985-01-31 | Sumitomo Chem Co Ltd | 新規なβ−ラクタム化合物及びその製造法 |
CA1283906C (en) * | 1983-05-09 | 1991-05-07 | Makoto Sunagawa | .beta.-LACTAM COMPOUNDS AND PRODUCTION THEREOF |
JPS60233076A (ja) * | 1984-05-03 | 1985-11-19 | Sumitomo Chem Co Ltd | 新規なβ−ラクタム化合物およびその製造法 |
KR880006244A (ko) * | 1986-11-24 | 1988-07-22 | 후지사와 도모 기찌 로 | 3-피롤리디닐티오-1-아자바이스클로[3.2.0]햅트2-엔-2-카르복실산 화합물 및 이의 제조방법 |
AU631671B2 (en) * | 1989-08-04 | 1992-12-03 | Banyu Pharmaceutical Co., Ltd. | 2-(2-vinylpyrrolidinylthio)carbapenem derivatives |
-
1992
- 1992-06-18 JP JP04159017A patent/JP3048196B2/ja not_active Expired - Fee Related
- 1992-06-19 WO PCT/JP1992/000790 patent/WO1993000344A1/ja active IP Right Grant
- 1992-06-19 AT AT92913257T patent/ATE224897T1/de not_active IP Right Cessation
- 1992-06-19 RU RU93058465/04A patent/RU2091381C1/ru not_active IP Right Cessation
- 1992-06-19 ES ES92913257T patent/ES2184731T3/es not_active Expired - Lifetime
- 1992-06-19 KR KR1019930703980A patent/KR100189667B1/ko not_active IP Right Cessation
- 1992-06-19 EP EP92913257A patent/EP0641795B9/en not_active Expired - Lifetime
- 1992-06-19 CA CA002111974A patent/CA2111974C/en not_active Expired - Fee Related
- 1992-06-19 DE DE69232791T patent/DE69232791T2/de not_active Expired - Fee Related
- 1992-06-19 TW TW081104823A patent/TW201747B/zh active
- 1992-06-19 DK DK92913257T patent/DK0641795T3/da active
- 1992-06-19 AU AU20002/92A patent/AU659172B2/en not_active Ceased
-
1993
- 1993-12-17 FI FI935698A patent/FI101537B/fi active
- 1993-12-17 NO NO934670A patent/NO303636B1/no unknown
-
1995
- 1995-05-05 US US08/435,271 patent/US5559224A/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
EP0641795B1 (en) | 2002-09-25 |
DE69232791T2 (de) | 2003-05-15 |
FI101537B1 (fi) | 1998-07-15 |
ES2184731T3 (es) | 2003-04-16 |
DE69232791D1 (en) | 2002-10-31 |
NO934670L (no) | 1994-02-18 |
JP3048196B2 (ja) | 2000-06-05 |
KR940701395A (ko) | 1994-05-28 |
AU2000292A (en) | 1993-01-25 |
EP0641795A4 (en) | 1994-06-09 |
JPH05294969A (ja) | 1993-11-09 |
NO303636B1 (no) | 1998-08-10 |
CA2111974A1 (en) | 1993-01-07 |
NO934670D0 (no) | 1993-12-17 |
FI935698A0 (fi) | 1993-12-17 |
FI935698A (fi) | 1994-02-04 |
FI101537B (fi) | 1998-07-15 |
US5559224A (en) | 1996-09-24 |
CA2111974C (en) | 2001-07-24 |
ATE224897T1 (de) | 2002-10-15 |
TW201747B (ja) | 1993-03-11 |
AU659172B2 (en) | 1995-05-11 |
WO1993000344A1 (en) | 1993-01-07 |
EP0641795A1 (en) | 1995-03-08 |
RU2091381C1 (ru) | 1997-09-27 |
KR100189667B1 (ko) | 1999-06-01 |
DK0641795T3 (da) | 2003-01-20 |
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